Resveratrol inhibits bile acid-induced gastric intestinal metaplasia via the PI3K/AKT/p-FoxO4 signalling pathway.
Resveratrol inhibits bile acid-induced gastric intestinal metaplasia via the PI3K/AKT/p-FoxO4 signalling pathway.
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DOI：
10.1002/ptr.6915
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
Lu W;Ni Z;Jiang S;Tong M;Zhang J;Zhao J;Feng C;Jia Q;Wang J;Yao T;Ning H;Shi Y
胃肠化生（GIM）是胃癌必不可少的前恶性肿瘤。慢性炎症和胆汁酸反流是主要因素。作为肠道发育转录因子，尾侧相关同源盒2 （CDX2）在GIM中起关键作用。白藜芦醇具有潜在的化学预防和抗肿瘤作用。目的是探讨白藜芦醇对胆汁酸诱导的GIM的影响。我们证明白藜芦醇可以以时间和剂量依赖的方式降低CDX2在胃细胞系中的表达。signal Finder 45 - Pathway报告基因阵列和transsignal Protein/DNA阵列试剂盒证实，白藜芦醇可以提高叉头盒O4 （FoxO4）活性，而鹅脱氧胆酸（CDCA）可以降低FoxO4活性。此外，生物信息学分析表明FoxO4可以结合CDX2启动子，这些推测得到了染色质免疫沉淀（ChIP）实验的支持。白藜芦醇可以激活FoxO4并通过增加磷酸化- FoxO4核反位来降低CDX2的表达。白藜芦醇可通过PI3K/AKT通路增加FoxO4磷酸化。异位FoxO4表达可以上调FoxO4磷酸化，抑制CDCA诱导的GIM标记物表达。最后，我们发现p‐FoxO4和CDX2在组织阵列中呈负相关。本研究验证了白藜芦醇可以通过PI3K/AKT/p‐FoxO4信号通路减少胆汁酸诱导的GIM，并对胆汁酸反流引起的GIM具有潜在的逆转作用。
Gastric intestinal metaplasia (GIM) is the essential pre‐malignancy of gastric cancer. Chronic inflammation and bile acid reflux are major contributing factors. As an intestinal development transcription factor, caudal‐related homeobox 2 (CDX2) is key in GIM. Resveratrol has potential chemopreventive and anti‐tumour effects. The aim of the study is to probe the effect of resveratrol in bile acid‐induced GIM. We demonstrated that resveratrol could reduce CDX2 expression in a time‐ and dose‐dependent manner in gastric cell lines. A Cignal Finder 45‐Pathway Reporter Array and TranSignal Protein/DNA Array Kit verified that resveratrol could increase Forkhead box O4 (FoxO4) activity and that Chenodeoxycholic acid (CDCA) could reduce FoxO4 activity. Furthermore, bioinformatics analysis showed that FoxO4 could bind to the CDX2 promoter, and these conjectures were supported by chromatin‐immunoprecipitation (ChIP) assays. Resveratrol can activate FoxO4 and decrease CDX2 expression by increasing phospho‐FoxO4 nucleus trans‐location. Resveratrol could increase FoxO4 phosphorylation through the PI3K/AKT pathway. Ectopic FoxO4 expression can up‐regulate FoxO4 phosphorylation and suppress CDCA‐induced GIM marker expression. Finally, we found a reverse correlation between p‐FoxO4 and CDX2 in tissue arrays. This study validates that resveratrol could reduce bile acid‐induced GIM through the PI3K/AKT/p‐FoxO4 signalling pathway and has a potential reversing effect on GIM, especially that caused by bile acid reflux.
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影响因子：
13.3
作者：
Mofarrahi, Mahroo;Guo, Yeting;Hussain, Sabah N. A.
通讯作者：
Hussain, Sabah N. A.
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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转录因子FOXO4下调并抑制胃癌肿瘤增殖和转移
影响因子：
3.8
作者：
Su L;Liu X;Chai N;Lv L;Wang R;Li X;Nie Y;Shi Y;Fan D
通讯作者：
Fan D